O my Lord!

Open for me my chest (grant me self-confidence,

contentment and boldness). And ease my task for me: And make
loose the knot (the defect) from my tongue,(i.e. remove the
incorrectness from my speech), that they understand my speech.

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 LEVEL MBBS 2nd year
SUBJECT Neuroscience
Topic Serotonin

Lecture No. --
Dated February 2022
Revision Original

By Dr. Mehnaz Nuruddin Gitay

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 Serotonin

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 Learning objectives
At the end of lecture students should be
able to know,
• Chemistry of serotonin.
• Understand the role of serotonin in CNS.
• Understand the relationship of serotonin
and pain.
• Levels of serotonin.
• Function of serotonin.
• Serotonin toxicity

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 Neurotransmitters & Sleep
Neurotransmitters are divided into two categories:
• Excitatory
• Inhibitory
• – Energizing
• – Calming
• – Motivating
• – Relaxing
• – Provide focus • – Sleep inducing
• – Rev up the system • – Slow down the system
Excitatory neurotransmitters Inhibitory neurotransmitters
related to sleep: related to sleep:
• – Epinephrine (adrenalin) • – Serotonin
• – Norepinephrine (noradrenalin) • – GABA
• – Phenylethylamine (PEA) • – Taurine
• – Glycine
• – Glutamate
• – Histamine

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 Discovery of Serotonin
• Dr. Vittorio Erspamer was looking for substances capable of
causing smooth muscle contraction and identified such a
substance in an acetone extract of rabbit gastric mucosa in the
1930’s. He named this substance enteramine.
• In the late 1940’s the laboratory of Dr Irving Page down the
road at the Cleveland Clinic isolated a vasoconstricting
substance in serum and named it serotonin. The structure of
serotonin was reported in 1949. Around 1952 it was realized
that enteramine and serotonin were the same substance.
• In 1952 Dr Betty Twarog joined the Page lab at the Clinic to
test the idea that invertebrate neurotransmitters might also be
used as neurotransmitters in vertebrates. Her research resulted
in the identification of serotonin in the brain, which was
published in 1953.

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 Neurochemical anatomy of the
brain serotonin system
• The neurochemical anatomy of brain
serotonin neurons was first studied by
fluorescence histochemical detection of
the indoleamine by Dahlstrom and Fuxe.
In 1964 they reported the distribution of
serotonin neuron cell bodies using the B
nomenclature.

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 Biosynthesis
• Serotonin or 5-hydroxytryptamine is synthesized from L-tryptophan.
The quantity of tryptophan ingested daily is about 0.5 to 1g; the
recommended daily allowance is about 200 mg, of which only a
small part is converted into serotonin.
• In addition to the metabolic pathway leading to serotonin,
tryptophan is used in protein synthesis and it is transformed by
hepatic tryptophan pyrrolase, generally called tryptophan 2-3-
dioxygenase and by indolaleamine-2,3-dioxygenase, into N-
formylkynurenine then into kynurenine, precursor of xanthurenic
acid and nicotinic acid. Activity of tryptophan pyrrolase is increased
by cortisol, ethanol consumption and tryptophan intake. The
activity of indoleamine-2,3-dioxygenase increases during stimulation
of the immune system. The activation of these 2 enzymes of the
kynurenine pathway could reduce the amount of tryptophan
available for serotonin biosynthesis.

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 Transformation of tryptophan into serotonin
involves two steps:

• Hydroxylation in 5-hydroxytryptophan
catalyzed by tryptophan hydroxylase, which
is the rate limiting enzyme of the synthesis.
This enzyme requires for its activity the
presence of tetrahydrobiopterine, oxygen,
NADPH2 and a metal, iron or copper.
• Decarboxylation of 5-hydroxytryptophan is
catalyzed by L-aromatic amino acid
decarboxylase with pyridoxal-phosphate as
coenzyme.

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In the brain, serotonin biosynthesis depends on the
quantity of tryptophan which crosses the blood-brain
barrier. Only free plasma tryptophan, i.e. unbound to
albumin, penetrates into the brain; decrease of its free
ratio reduces its penetration. Moreover, other amino
acids are in competition with free tryptophan and limit
its entry in the brain. Plasma cortisol, whose level is
increased in depressed patients, decreases free L-
tyrosine and free L-tryptophan concentrations in
plasma, i.e. the forms which penetrate into the brain.
Insulin, of which secretion is increased by
carbohydrates, has an opposite effect and decreases the
concentration of the amino acids other than tryptophan.

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 Transformation of serotonin into melatonin, which should not be
regarded as a degradation pathway because melatonin is also
active, is carried out primarily in the pineal gland. It involves two
steps:

• Acetylation of the amine group by N-acetyl transferase leading

to N-acetyl-serotonin.
• Methylation of the OH group by 5- hydroxyindole-O-
methyltransferase catalyzing the transfer of a methyl group
from S-adenosyl-methionine to obtain acetyl-5-
methoxytryptamine or melatonin.
The concentration of melatonin in the pineal gland presents
circadian variations: it follows the variations of N-acetyl
transferase activity, increasing during the night and decreasing
during the day, darkness and light playing a regulatory role via
catecholamines. Light inhibits melatonin biosynthesis.

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Serotonin is found in many tissues:
• In the digestive tract which contains about 95% of the total amount of
serotonin of the body, localized in enterochromaffin cells.
• in the central nervous system of all species: higher concentrations are found
in brainstem than in cortex. Serotonin, released by presynaptic serotonergic
neurons in synaptic clefts, activates specific receptors and is partly
reuptaken by presynaptic neurons.
• In platelets: practically all blood serotonin (concentration going from 100
to 200 micrograms per liter) is found in platelets which do not synthesize it,
but take it from plasma where it is released by enterochromaffin cells. The
uptake of serotonin by platelets is very fast. The half-life of serotonin in
platelets is the same as that of platelets, i.e. five or six days. Serotonin
released from platelets in plasma has a relatively localized effect on the
vessels where it is released, for example during migraine.
The half-life of serotonin is long in platelets and intestine, and very short, a
few minutes, in the brain. The concentration of a compound in an organ, static
view of a dynamic phenomenon, is not necessarily a good representation of
metabolic activity and turn-over.

Melatonin found in plasma is released from the pineal gland. Its plasma
concentration decreases during ageing.
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 Inactivation
Serotonin is converted into inactive molecules by
biotransformations:
• Oxidative deamination of the lateral amino chain by
monoamine oxidase, leading to 5-hydroxy-indol-
acetaldehyde which is then oxidized into 5-hydroxy-
indol-acetic acid (5-HIAA) found in urines in quantities
normally lower than 10 mg/24 h.
• Conjugation by glucuronic acid or sulfate of the
hydroxyl group OH in 5-position .

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 Serotonin and Pain
• Serotonin acts on a total of 14 receptor
subtypes, receptor subtype 1A being to
date one of the best characterized. The
serotonin 5-HT1A receptor is expressed
as an autoreceptor in raphe nuclei, and
thus is a key regulator of brain
serotonergic neurotransmission.
• Serotonin 5-HT1A receptors control pain
both in the spinal cord and in the brain.

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• Several brain areas involved in pain
perception, such as the raphe nuclei,
amygdala, cingulate cortex, insula and
prefrontal cortex (Bushnell & Apkarian
2006, Casey & Tran 2006), have a high
density of 5-HT1A receptors (e.g.
Azmitia et al. 1996, Hirvonen et al.
2007, Palacios et al. 1990, Parsey et al.
2002, Pazos & Palacios 1985, Rabiner et
al. 2002, Tiihonen et al. 2004), as
indicated by studies in non-human
primates and humans.
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• Serotonin is a chemical substance that is
located in the brain and a neurotransmitter
that has an effect on the amount of pain
that a person can withstand.
• Serotonin normally reduces the intensity of
pain signals sent to the brain.
• Serotonin level, can have an effect on pain
threshold too.
• Because serotonin helps keep ‘pain gates’
closed, a lack of it can make you feel more
pain
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 Regulation of circadian rhythms
and the sleep–wake cycles
Similar to the regulation of visceral
activity and body temperature,
regulation of sleep is mediated by
opposing actions of the anterior
and posterior/lateral regions of the
hypothalamus.

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 Insomnia
• Insomnia is difficulty falling and/or staying asleep
• The major cause of insomnia is the failure of the
body to produce sufficient amounts of the
neurotransmitter melatonin. This chemical induces us
to sleep in conditions of total darkness. Thus an
appropriate dark room is one necessary condition.
The bedroom should never be used for reading or
watching television. When you happen to go to the
bathroom in the middle of the night, try to do so in
the dark. Don’t switch on the light as this will switch
off melatonin production. Melatonin production also
decreases with age.

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 Sleep Apnea
• Since the 1950's it is known, that serotonin has a regulating
effect on the sleep-wake cycle. However, the studies concerning
the mechanisms of this regulatory effect have long been
contradictory. Recent studies have shown, that serotonin
primarily influences the wake periods through the activity of
the serotonin containing neurons in the hypothalamus. During
sleep this activity is reduced and almost stops during REM. An
increase as well as a decrease in the serotonin level can cause
disruptions in the sleep-wake cycle and therefore have a strong
influence on the exposure to sleep apnea.
• The nerves that control breathing need a certain amount of
serotonin in order to communicate with the brain. An
improperly-working serotonin system deprives the body of an
adequate supply of the neurotransmitter, often resulting in
sleep apnea. Also, serotonin receptors control the release of
hormones such as cortisol. One role of cortisol is to help control
the muscles needed for breathing.

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 • Numerous drugs and drug combinations have been reported
to produce serotonin syndrome.
• Diagnosis of serotonin syndrome includes observing the
symptoms produced and a thorough investigation of the
patient's history
• The syndrome has a characteristic picture but can be
mistaken for other illnesses in some people, particularly those
with neuroleptic malignant syndrome.
• No laboratory tests can currently confirm the diagnosis.
• Treatment consists of discontinuing medications which may
contribute and in moderate to severe cases administering a
serotonin antagonist.
• An important treatment includes controlling agitation with
benzodiazepine sedation.

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Thank You

Lecture by Dr. Mehnaz Nuruddin Gitay

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